The discovery of bioactive small molecules has emerged as a major theme in academic research and is central to the NIH Roadmap initiative. Using modest equipment and a unique collection of natural and synthetic compounds, we have established a vibrant small molecule screening program at UCSC that has yielded fruitful results. Our current screening throughput, however, is far too slow to keep pace with our expanding compound collection. The Crews lab's natural product collection has grown substantially with the recent implementation of new high-throughput purification techniques, and the acquisition of commercial and private compound libraries will bring our total in-house collection to more than 50,000 by the end of this year. Our current screening lab consists of a manual compound transfer device and low throughput liquid handling equipment capable of performing operations on one plate at a time. This proposal is to request high-throughput screening (HTS) equipment for the establishment of a state-of-the-art screening facility at UCSC. Based on the screens proposed, this facility will lead to the identification of novel small molecule probes of the following biological processes: cell cycle checkpoints, cell growth, RNA splicing, transcription elongation, chromatin remodeling, inflammation (due to lipoxygenase activity), actin dynamics, bacterial biofilm formation, malaria infection, and cytokinesis. The creation of a modern HTS facility at UCSC will thus facilitate the discovery of potential therapeutic leads and drug targets related to a variety of disease states. Relevance: High throughput screening is expected to have a major impact in small molecule probe discovery in the public sector just as it has played a role in speeding up drug lead discovery in industry. In order to bring this goal to fruition, integrated HTS equipment must be available to researchers for the validation and implementation of screens in high throughput format. [unreadable] [unreadable] [unreadable]